By Michael E. Speer, MD

Introduction – Ballantyne first described Hydrops fetalis or edema of the fetus in 65 human fetuses or newborn infants in 1892. Potter, in 1943, subdivided hydrops fetalis into immune and non-immune categories based upon the presence or absence of Rhesus isoimmunization.

Definitions – Hydrops fetalis is usually defined as the presence of subcutaneous tissue edema and the collection of fluid in one or more body cavities. (e.g., placenta, peritoneal space, pericardial sac). Immune hydrops occurs in the presence of fetoma-ternal isoimmunization, the most common of which is Rhesus isoimmunization; non-immune hydrops results from non-immune pathophysiology.

Incidence – In 1970, Macaffe et al re-ported that 82% of fetal hydrops were a result of isoimmune disease [1]. Since the implementation of antenatal Rh(D) immune globulin prophylaxis in the 1960's, the inci-dence of maternal Rh alloimmunization has fallen significantly. Recent reviews indicate that greater than 90% of fetal hy-drops are now due to non-immune causes [2]. Although the rate of hydrops in the general population approximates 1 in 4000 pregnancies, the incidence in selected pregnancies referred for ultrasonography to a perinatal center is as high as 1 in 160

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INSIDE THIS ISSUE

Immune and Non-Immune Hydrops Fetalis by Michael E. Speer, MD ~Page 1

Summary of the 3rd Annual Evidence vs. Experience in Neonatal Practices Conference: June 16th and 17th, 2006 By Istvan Seri, MD, PhD ~Page 7

DEPARTMENTS

Medical Meetings, Symposiums and Conferences ~Page 6

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to 1 in 540 pregnancies [3]. The incidence of immune hydrops in the same population is lower and is estimated to occur between 1 in 1256 and 1 in 3473 [3].

Pathogenesis – Previously the patho-physiology of both non-immune and im-mune hydrops fetalis was attributed to a variety of conditions including hypopro-teinemia, cardiac failure, increased capil-lary permeability, portal venous obstruction or malformation of the lymphatic system. When the various proposed causes of hy-

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IMMUNE AND NON-IMMUNE HYDROPS FETALIS Volume 1 / Issue 4 August 2006

“Hydrops fetalis has been reported in association with many conditions. Ultrasound and pathological studies performed early in gestation have found a predominance of chromosomal abnormalities, particularly aneuploidy, associated with non-immune hydrops fetalis”

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drops are examined carefully, it becomes apparent that the “causes” listed in many reports are cursory in nature and do not address the underlying pathophysiology of the condition or do not define hydrops fetalis as described above.

Lymphatic function – In virtually all cases, hydrops fe-talis results from an interference with lymphatic function either because of a structural anomaly of lymphatic devel-opment (e.g., cervical hygroma, pulmonary lymphangiec-tasia) adversely impacting lymphatic drainage [4,5] or ele-vated central venous pressure preventing normal lymph flow. The latter may be due to cardiac compression result-ing in elevated central venous pressure due to mass ef-fect (e.g., congenital cystic adenomatoid malformation, congenital high airway obstruction syndrome) or low or high output heart failure (e.g., cardiac arrhythmia, con-genital heart disease, hemangioma, anemia, twin-twin transfusion syndrome). Many chromosomal and storage diseases either have myocardial dysfunction, structural heart disease, particularly narrowing of the aortic arch, severe anemia, or other causes of elevated central ve-nous pressure associated with the primary disease. Ane-mia alone does not appear to cause hydrops fetalis; only when central venous pressure rises does hydrops occur [6]. Likewise congenital or induced hypoproteinemia does not seem to cause in utero hydrops [7].

Hypoxia – Recent work by Lumbers et al, have shown that a severe in utero asphyxial insult in the premature fetal sheep causes hydrops. There is sustained activation of the renin-angiotensin system and elevated renal renin levels without elevated central venous pressure or evi-dence of renal failure [8]. In this instance, hydrops may be a result of a hypoxic endothelial injury that interferes with both nitric oxide and cyclic guanosine monophosphate production.

Associations – Hydrops fetalis has been reported in as-sociation with many conditions [Table]. Ultrasound and pathological studies performed early in gestation have found a predominance of chromosomal abnormalities, particularly aneuploidy, associated with non-immune hy-drops fetalis. The exception is in Asia, where a majority of cases are associated with alpha thalassemia. Studies car-ried out later in pregnancy have found that other congeni-tal anomalies predominate, particularly cardiac, either functional or structural. The incidence of “idiopathic” hy-drops fetalis ranges between 3.9&% and 35% and is be-

coming less frequent a diagnosis. It also should be re-membered that any condition that causes fetal death may have hydrops fetalis either as a terminal event reflecting ongoing myocardial failure or severe anoxic injury as de-scribed by Lumber and coworkers [8].

Evaluation – A thorough evaluation of the fetus with hy-drops fetalis is warranted to determine possible therapeu-tic options, keeping in mind the potential hazards of fetal intervention to both fetus and mother. This is particularly true in early gestation given the high risk of fetal demise. The parents should be counseled that prenatal testing for viral, hematological, genetic, and biochemical causes will provide a more accurate evaluation of the pathogenesis than if one attempts to perform these studies on a still-born infant [6]. Early identification of a disorder with a poor prognosis will allow the parents to terminate the pregnancy with the least risk to the mother, if they so wish.

Critical examination of available data suggests that the fetal risk of first trimester chorionic villus sampling (CVS) and midtrimester amniocentesis are equal and approxi-mate 1% [9]. Polymerase chain reaction (PCR) testing has dramatically expanded the ability to test for both genetic mutations and intrauterine infection. One disadvantage of CVS compared with amniocentesis is the approximately 1% risk of placental mosaicism. Also, CVS does not allow for assessment of amniotic fluid alpha-fetoprotein or ace-tylcholinesterase. Both CVS and amniocentesis can result in maternal-fetal hemorrhage and isoimmunization and Rhogam is indicated for Rh-negative women. CVS should probably be avoided in patients who are already isoimmu-nized because amniocentesis is less likely to cause a fur-ther elevation in their antibody titer. Amniocentesis has been associated with maternal-fetal transmission of HIV as well as hepatitis B and C viruses although the exact risks are presently unknown. The mortality following fetal blood sampling is considerably higher, particularly in cases involving nonimmune fetal hydrops. Fetal hemor-rhage, fetal bradycardia, cord hematoma, arterial vaso-spasm, and fetal death have been reported. Other risks include ruptured membranes, bleeding, and preterm labor.

Total body sonography as well as detailed fetal echocardi-ography is indicated to detail whether congenital somatic or cardiac anomalies with or without cardiac failure are present. If questions exist as to the presence of fetal ane-mia, Doppler measurement of peak velocity of systolic blood flow in the middle cerebral artery should be per-

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formed. Depending upon the past medical history and racial background of the family, hemoglobin electropho-resis and DNA genotyping (i.e., alpha thalassemia) may be indicated. Ma-ternal blood type testing and antibody screening for RBC antigens will assist in the diagnosis of immune mediated anemia. Kleihauer-Betke acid elution will determine the presence of fetal-maternal hemorrhage. Serologic test-ing for infectious agents have limited value although may lead to a diagno-sis of recent infection (e.g., specific IgM titers, MHA-TP). The introduction of real time PCR testing will likely re-place viral cultures and serologic evaluation as the evaluation of choice. Likewise, array-comparative genomic hybridization (array-CGH) has the po-tential to replace karyotype banding analysis. Array-CGH is a genome-wide screening strategy for detecting DNA copy number imbalances that can be rapid, less labor-intensive, and it is highly amenable to automation.

Mortality & In Utero Therapy – Mor-tality totally depends upon the under-lying cause. Generally, the mortality rate for hydrops identified in the first part of pregnancy is higher than the mortality of patients diagnosed with hydrops in the latter portion, due to the high incidence of lethal malforma-tions and chromosomal defects in those fetuses [2,3,9]. Diagnosis of fetal hydrops prior to 24 weeks’ of pregnancy with later delivery carries a mortality rate of 94% to 96%.

If the major disease states associated with fetal hydrops are each examined

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Table: Conditions associated with Elevated Central Venous Pressure and Nonimmune Hydrops Fetalis.

Etiology Fetal Condition Low Output Cardiac Failure or Venous Obstruction Chromosome with or without Complex Congenital Heart Defect

* Sex Chromosome Aneuploidy (45,X; 45,X/46,XX; 45,X/46,XY) * Tetrasomy * Triploidy * Trisomy 18 * Trisomy 13 * Trisomy 21 Cardiac Arrhythmia * Atrial Flutter * Heart Block * Sinus Bradycardia * Supraventricular Tachycardia Complex Congenital Heart Disease * Pulmonary Valve Atresia or Incompetence * Tricuspid Valve Incompetence * Aortic Valve Stenosis or Atresia * Hypoplastic Left Heart Syndrome * Truncus Arteriosus Endocardial Fibroelastosis

Inborn Errors of Metabolism * Carnitine Deficiency * Disseminated Lipogranulomatosis (Farber Disease) * Galactosialidosis * Gaucher Disease, Type 2 * GMI Gangliosidosis * Hypothyroid * ~Infantile Sialic Acid Storage Disease (ISSD) * Mucolipidosis II (I-cell Disease) * ~Mucopolysaccharidosis VII * Mucopolysaccharidosis IVA * Myopathies * Lethal Multiple Pterygium Syndrome * Mitochondrial Trifunctional Protein Deficiency * Myotonic Dystrophy * Nemaline Rod Myopathy * Niemann-Pick Disease Type C * Sialisis . . ~ hydrops is common

Myocarditis * Adenovirus * Coxackie Virus * Cytomegalovirus * Enterovirus * Parvovirus

Mass Effect * Achondrogenesis * Chondrodysplasia * Congenital Diaphragmatic Hernia * Congenital High Airway Obstruction Syndrome * Cystic Adenomatoid Malformation * Cystic Hygroma Colli * Cytomegalovirus * Herpes Virus * Infantile Cortical Herperostosis * Leiomyosarcoma * Omphalocele * Pulmonary Sequestration * Syphilis * Teratoma * Toxoplasmosis * Rhabdomyoma * Midaortic Syndrome

“Because of the high incidence of neurologic injury that may occur in utero, neurodevelopmental follow-up should occur in all cases”

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the fetus can be treated in utero, po-tentially reversing the hydropic state. Hydrops secondary to structural heart disease, chromosomal or syndromic conditions is almost always lethal [9]. Survival with fetal hydrops due to in-fection is also poor, with a mortality approaching 80% [9].

The prognosis of the fetus with ane-mia depends upon the etiology of the anemia. Mortality associated with al-pha thalassemia is virtually 100%; the mortality associated with fetal parvovi-rus infection approximates 10%. The survival rate of nonhydropic fetuses with rhesus alloimmunization has been reported to be 92%, while survival in hydropic infants ranges between 70% and 78% [10].

Outcome –Those infants who survive the perinatal period usually will have a normal developmental outcome, but not always. In 34 cases of 78 fetuses with hydrops where intrauterine ther-apy was provided (11 with hydrotho-rax, 6 with supraventricular tachycar-dia, 6 with isoimmunization and 5 with anemia secondary to parvovirus infec-tion), 24 of those infants survived the neonatal period. The highest survival rate was found in those patients re-ceiving intravascular blood transfu-sions (i.e., isoimmunization and parvo-virus anemia) [3]. Infants with twin-twin transfusion syndrome are fre-quently delivered prior to 30 weeks gestation and their prognosis is less sanguine. Of 12 hydropic infants re-ported by Matsuda and Kouno, two thirds died and, of the survivors, half had cerebral palsy [11].

Neonatal Management – In spite of significant advances in neonatal treat-ment, including steroids, surfactant, and advanced ventilator care, the mor-tality rate of live born infants with hy-

NEONATOLOGY TODAY 5 AUGUST 2006

High Output Cardiac Failure Immune Anemia * ABO Incompatibility * Anti C * Anti c * Anti D * Anti E * Anti e * Anti-Js(b) * Anti K * Anti Mur * Anti PP1Pk * Kell Nonimmune Anemia * Alloimmune Thrombocytopenia * Alpha Thalassemia * Erythroleukemia * Congenital Dyserythropoietic * Eythrocyte Pyruvate Kinase Deficiency * Fetomaternal Hemorrhage * G-6-PD Deficiency * Glucose Phosphate Isomerase Deficiency * Gunther’s Disease * Hemochromatosis * Hemoglobin Taybe * Hereditary Stomatocytosis * Hereditary Spherocytosis * Intrauterine Hemorrhage, Fetal * Infection * Chagas’ Disease * Cytomegalovirus * Parovirus * Syphilis * Toxoplasmosis Arteriovenous Malformation: * Chorioangiomata * Hemangioendothelioma * Intracranial Tumor * Sacrococcygeal teratoma * Twin-Twin Transfusion Syndrome * Vein of Galen

Fetal Methemoglobinemia Hyperthyroidism Renal Vascular Hypertension (Midaortic Syndrome)

Etiology Fetal Condition

Table: Conditions associated with Elevated Central Venous Pressure and Nonimmune Hydrops Fetalis (Continued from previous page).

independently, mortality varies mark-edly from category to category and emphasizes the importance of prena-tal studies to accurately identify the

underlying diagnosis. For example, of all cardiac causes of hydrops, hy-drops due to cardiac tachyarrhyth-mias carries the best prognosis as

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drops fetalis remains at approximately 50% in recently reported series [3]. In order to optimize outcome as much as possible, delivery of such fetuses should occur in tertiary centers with an equivalent level of neonatal care. Simi-lar studies to those performed to evalu-ate fetal hydrops should be undertaken here to identify possible recurrent causes of hydrops and to provide counseling to the parents. Because of the high incidence of neurologic injury that may occur in utero, neurodevelop-mental follow-up should occur in all cases.

References

1. Macafee, CA, Fortune, DW, Belscher, NA. Non-immunological Hy-drops fetalis. J Obstet Gynaecol Br Commonw 1970; 77:226-37.

2. Ismail, KM, Martin, WL, Ghosh, S, et al. Etiology and outcome of hy-drops fetalis. J Matern Fetal Med 2001; 10:175.

3. Sohan, K, Carroll, SG, De La Fuenta, S, et al. Analysis of outcome in hydrops fetalis in relation to gesta-tional age at diagnosis, cause and treatment. Acta Obstet Gynecol Scand 2001; 80:726.

4. Swartz, MA, Kaipainen, A, Netti, PA, et al. Mechanics of interstitial-lymphatic fluid transport: theoretical foundation and experimental valida-tion. J Biomech 1999; 32:1297.

5. Boardman, KC, Swartz, MA. Inter-stitial flow as a guide for lymphangio-genesis. Circ Res 2003; 92:801.

6. Blair, DK, Vander Straten, MC, Gest, AL. Hydrops in fetal sheep from rapid induction of anemia. Pediatr Res 1994; 35:560.

7. Moise AA, Gest AL, Weickmann PH, McMicken HW. Reduction in

plasma protein does not affect body water content in fetal sheep. Pediatr Res. 1991;29:623-6.

8. Lumbers, ER, Gunn, AJ, Zhang, DY, et al. Nonimmune hydrops fe-talis and activation of the renin-angiotensin system after asphyxia in preterm fetal sheep. Am J Physiol Regul Integr Comp Physiol 2001; 280:R1045.

9. Bukowski, R, Saada, GR. Hydrops fetalis Clinics in Perinatol. 2000; 27:1007.

10. Moise, KJ Jr. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2002; 100:600.

11. Matsuda, Y, Kouno, S. Fetal and neonatal outcomes in twin oligohy-dramnios-polyhydramnios sequence including cerebral palsy. Fetal Diagn Ther 2002; 17:268.

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Michael E. Speer, MD Professor of Pediatrics Baylor College of Medicine 6621 Fannin WT 6 - 104 Houston, TX 77030 USA mspeer@bcm.tmc.edu

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MEDICAL MEETINGS, SYMPOSIUMS AND

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Obstetric Challenges for Contemporary Practice 2006 Sep. 29, 2006; Denver (Bloomfield), CO USA www.pediatrix.com

2006 AAP National Conference & Exhibition Oct. 7-10, 2006; Atlanta, GA USA http://s12.a2zinc.net/clients/aap2005/aap2005/public/enter.aspx

Europaediatrics Oct. 7-10, 2006; Barcelona, Spain www.kenes.com/europaediatrics/

NANN 22nd Annual Educational Conference—Neonatal Nursing Excellence: Growing and Knowing Nov. 8-11, 2006; Nashville, TN USA www.nann.org

30th Annual Neonatal International Symposium –Neonatology 2006 Nov. 8-11, 2006; Miami Beach, FL USA neonatology.med.miami.edu/conference/default.htm

Hot Topics in Neonatology 2006 Dec. 2-5, 2006; Washington, DC USA www.hottopics.org

NEO-The Conference for Neonatology Feb. 7-10, 2007; Orlando, FL USA www.neoconference2007.com/

Evidence vs. Experience in Neonatal Practices Jun. 22-23, 2007; Chicago, IL USA www.5StarMedEd.org/neonatal

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SUMMA RY O F T H E 3R D A N N UA L EV ID E N C E V S . EX P E R IE N C E IN NE O N ATA L PR AC T IC E S CO N FE R E N C E: JU N E 16T H A N D 17T H, 2006

By Istvan Seri, MD, PhD

The third annual Evidence vs. Experi-ence in Neonatal Practices CME Con-ference was held at the Hyatt Harborside in Boston, MA on June 16th and 17th, 2006. The conference, initi-ated in 2004, was co-sponsored by the Keck School of Medicine of the Univer-sity of Southern California and the Annenberg Center for Health Sciences at Eisenhower. Focusing on the clini-cal needs of neonatal practitioners to examine current and developing treat-ment options for the care of critically ill, preterm infants, this program reviewed the current level of evidence and prac-tical experience linked with treatment protocols for these patients.

The program content and faculty was the task of the 2006 steering commit-tee - Istvan Seri, MD, PhD, Jatinder B h a t i a , M B B S , R a n g a s a m y Ramanathan, MD and Kris Sekar, MD. The committee assembled a world-class faculty, who focused on bringing the “state of the art” in neonatal prac-tice along with a practical orientation that the participants could consider utilizing in their practice after the con-ference.

DEY, L.P., the U.S. distributor of Curosurf®, has supported this program since its inception with unrestricted educational grant support. This year’s event acquired additional support from Mead Johnson Nutritionals.

2006 Attendance Reflects Strong Interest

This year’s conference had a turnout of 137 attendees, which included 29 fel-lows plus an additional 13 faculty. While registration fees are routinely waived for all fellows who attend the conference, 23 fellows received addi-tional Neonatal Practices Fellow Schol-arships from the Annenberg Center to attend the conference. This support was made available via an unrestricted grant by DEY, L.P.

These figures reflect a growth in atten-dance over the years. In 2004, there were 108 participants including 14 fac-ulty at the inaugural meeting in Chicago. In 2005, there were 106 indi-viduals, including 11 faculty and 30 fellows, who took part in the San Diego meeting. The growing popularity of this event is attributable to the nature of the content whereby the most important and clinically relevant questions in neo-natology are presented, and the topics

Evidence vs. Experience 2006 Steering Committee Colleagues, left to right: Kris Sekar, MD; Jatinder Bhatia, MBBS; and Rangasamy Ramanathan, MD.

discussed are critically examined for the presence of evidence or if there is only experience. This “compare and contrast” format is made possible by the interaction of the audience with the internationally recognized faculty who bring tremendous practice insight and

clinical and research expertise to the event.

Conference Highlights

The Evidence vs. Experience in Neo-natal Practices conference was divided into four sessions, spread over two days. This year’s keynote presentation “Permissive Hypercarbia and Hypoxe-mia in Newborns” was provided by Waldemar A. Carlo, MD from the Uni-versity of Alabama. Dr. Carlo pre-sented information from randomized control trials, as well as studies investi-gating the cellular and organ-system effects of hypercarbia and hypoxemia in the preterm neonate. The findings suggest a relationship between permis-sive hypercapnia and lung injury and abnormal cerebral blood flow regula-tion. As for the question of tissue oxy-

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AUGUST 2006 8 NEONATOLOGY TODAY

Therapy and Noninvasive Ventilation.” He reviewed the findings on short and long-term outcomes associated with the use of the different surfactant prepara-tions and compared the available data between natural and synthetic surfac-tants. Dr. Ramanathan critically exam-ined the available evidence presented by the various surfactant trials where face to face comparisons between differ-ent surfactant preparations were made. He also mentioned that there is some evidence that the use of poractant alfa (Curosurf®; DEY, L.P., Napa, CA) may be associated with decreased neonatal mortality and fewer administered doses compared with beractant (Survanta®; Ross Laboratories, Columbus, OH). However, he warned that more data is needed before a final conclusion could be reached regarding these findings. Dr. Ramanathan then indicated that, based on the available evidence, avoidance of intubation appears to be associated with a decline in the incidence of bronchopul-monary dysplasia (BPD). However, he warned that it remains to be seen whether patients tolerating CPAP from the beginning represent a population of decreased disease severity, which then contributes to the decreased incidence of BPD in the “non-intubated” VLBW

genation, Dr. Carlo pointed out the potential toxicity associated with the use of higher inhaled oxygen concen-trations. He then summarized the data on the use of lower oxygen satura-tions in very low birth weight (VLBW) neonates and offered target values to be employed in this patient popula-tion. The take-home message was that most current data suggested that oxygen saturations in the mid-to high 80s and low 90s are sufficient for pre-term infants, and that additional oxy-gen supplementation may worsen pulmonary outcomes and increase the risk of ROP (retinopathy of prematur-ity). Current oxygen saturation tar-gets generally utilized in clinical prac-tice may be too high, and permissive hypoxemia may be advantageous in neonatal respiratory care. However, he warned that appropriately de-signed prospective randomized clini-cal trials are needed before firm rec-ommendations can be made on the most desirable levels of oxygen satu-ration and PaCO2 in the VLBW patient population.

Session 1: Pain Management

Two complementary talks were pre-s en t ed w i t h i n t h i s s es s i o n : “Pharmacologic Management of Pain and Sedation in the NICU” by K.J.S. Anand MBBS, DPhil from the UAMS C o l l e g e o f M e d i c i n e , a n d “Nonpharmacologic Management of Pain in the NICU” by Björn Westrup, MD, PhD, Karolinska University Hos-pital-Danderyd, Stockholm, Sweden.

First, Dr. Anand summarized the available data regarding the admini-stration, safety and effectiveness of different analgesic medications to the neonate. The level of evidence per-taining to these medications on short and long-term outcomes, as well as potential side effects, was then sys-tematically presented.

Next, Dr. Westrup focused primarily on the findings of the Newborn Indi-vidualized Development Care and Assessment Program (NIDCAP) and

indicated that the use of developmen-tally appropriate nursing and medical care focusing on decreased stress and pain may enhance neurodevelopment and result in a decrease in the use of pharmacological agents. He empha-sized the importance of the suggested positive impact of such care on mental and motor development, long-term be-havior, performance intelligence, and mother-infant interaction.

Session 2: Noninvasive Ventilation Strategies and Surfactant Support

Discussion of noninvasive ventilation strategies was the focus of Session 2 during the conference. Roger Soll, MD, University of Vermont, College of Medicine, provided a meta-analysis overview of the available data on the use, safety and efficacy of noninvasive ventilation techniques in preterm neo-nates. Dr. Soll concluded that, in pre-term infants with RDS, the application of continuous positive airway pressure (CPAP), has been associated with re-duced mortality and that nasal intermit-tent positive pressure ventilation (NIPPV) is a useful method of respira-tory support that augments the benefi-cial effects of nasal CPAP in preterm infants with significant evidence indi-cating that its use leads to a decrease in extubation failure.

Next, Dr. Ramanathan of the Keck School of Medicine of the University of Southern California in Los Angeles, CA presented his talk “Early Surfactant With permission - Nature Publishing Group

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NEONATOLOGY TODAY 9 AUGUST 2006

patient population. In the latter part of the presentation, Dr. Ramanathan compared different types of noninva-sive ventilations, including different nasal CPAP interfaces, and dis-cussed using non-intubation ventila-tion modes with modalities such as nasal IPPV (NIPPV). In closing, Dr. Ramanathan concluded that there is evidence that early CPAP in the de-livery room is beneficial for the ex-tremely low birth weight neonate.

Examining BPD in Detail

Christian P. Speer, MD, FRCPE, of the University Children’s Hospital Wurtzburg, Germany, examined the pathophysiology of BPD in greater detail. Dr. Speer afforded a detailed review of the mechanisms of early injury of the developing lung, and addressed the question of whether or not higher oxygen concentrations could contribute to the development of BPD. Dr. Speer concluded that there is enough evidence to suggest that oxygen toxicity is indeed a sig-nificant factor in the development of

BPD. Further, Dr. Speer reported that prophylactic indomethacin does not prevent BPD, and suggested that diuretics, caffeine, steroids, Vitamin A, inhaled nitric oxide or potentially any strategy to reduce inflammation in the airways and pulmonary tissue could help prevent BPD.

Session 3: Exploring Asphyxia and Brain Death

Session three, moderated by Dr. Sekar from the University of Okla-homa Health Sciences Center, in-cluded discussions pertaining to peri-natal asphyxia. Jeffrey Perlman, MB, ChB, from the Medical College of Cornell University, NY discussed the pathophysiology of hypoxic-ischemic encephalopathy (HIE). Dr. Perlman reviewed the factors contributing to the development of brain injury and the pathophysiology of hypoxic ischemic brain damage at the mo-lecular and cellular level. Dr. Perlman stated that, although the pathogene-sis of perinatal brain injury is com-plex, many of the contributing path-

ways of potential injury have been successfully studied. He concluded that, based on the available evi-dence, the majority of infants that are at potential risk for brain injury will not suffer brain damage, thereby indicating that a substantial adaptive mechanism is present even in the developing brain.

“Head and Body Cooling in the As-phyxiated Newborn” was the ensuing discussion presented by Richard A. Polin, MD, from Columbia University, New York, NY. Dr. Polin’s discus-sion, sub-titled "Experiments in Hu-man Refrigeration” reviewed the his-torical uses of hypothermia and pro-vided evidence that hypothermia has the capability to preserve cerebral metabolism under conditions of de-creased oxygen delivery. Dr. Polin reviewed the results of the CoolCap trial, and concluded that there was a benefit only to those infants who had less severe injury indicated by mod-erately affected amplitude integrated EEG changes. He then reviewed the findings of the whole body hypother-mia trial for neonates with HIE and questioned whether induced hypo-thermia should become routine ther-apy for the neonate following hy-poxic ischemia. He concluded that, while cooling is relatively safe, it should only be done by individuals who are appropriately trained and under well-defined clinical protocols as the effect of cooling on mortality and morbidity remains uncertain. Finally, he stressed that infants that are candidates for cooling should be identified as quickly and precisely as possible.

In the last presentation of this ses-sion, Dr. Sekar presented his talk “Brain Death in the Newborn.” Dr. Sekar reviewed the available clinical data, and the consensus among caregivers, families and society and stated that it would be prudent if brain death were determined based on repeated clinical examination, with particular attention to brain

Respiratory advances in the management of neonates: bubble CPAP. With permission: R. Ramanathan, MD.

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AUGUST 2006 10 NEONATOLOGY TODAY

Program Publication and More to Come in 2007

As with the first two conferences, the proceedings from this year’s confer-ence will be published in the Journal of Perinatology (www.nature.com/jp/ journal/v26/n1/abs/7211409a.html). The quality of the presentations has resulted in two outstanding supple-ments which have been distributed during the past two PAS/SPR meet-ings. The steering committee will be working with faculty and Gil Martin, MD, supplement editor for the Journal, to bring forth this year’s proceedings in the spring of 2007.

The next “Evidence vs. Experience in Neonatal Practices Conference” will be held in Chicago, IL on June 22nd and 23rd, 2007 returning to the city of the inaugural meeting. As it becomes available, more information regarding the 2007 program can be obtained at t h e m e e t i n g w e b s i t e a t www.5StarMedEd.org/neonatal or by calling Nina Pratt at 760-773-4500 or toll free at 800-321-3690, 8:00 am to 5:00 pm, Pacific Time. All neonatolo-gists, neonatal nurse practitioners, physician assistants, and neonatal fellows are invited and encouraged to attend next year’s event carrying on with the tradition of providing the most up-to-date, state-of-the-art and clini-cally relevant information for the care of the preterm and term neonate.

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stem reflexes, apnea test, EEG, and cerebral blood flow examinations. He also suggested that, if the EEG is isoelectric or if cerebral blood flow is absent, the observation period can be shortened from the suggested 48 hours. Dr. Sekar summarized his talk by pointing out that religious beliefs, cultural issues, and legal ethical consid-erations make this topic extremely com-plex and not only medically related as it concerns the immediate and extended family, as well as society in general.

Session 4: Review of Nutritional Issues and Controversies

Dr. Bhatia, from the Medical College of Georgia, discussed human milk and the premature infant to open the final session. He reviewed the bene-fits of human milk and the limiting nutrients present in human milk for the VLBW neonatal patient popula-tion. He emphasized that, in the VLBW neonate, the sole use of hu-man milk has been associated with poorer growth and metabolic bone disease and, therefore, fortification of human milk in this patient population has become an accepted concept.

Two final discussions entitled “Nutritional Support and BPD” and “Controversies in Neonatal Nutrition: DHA and Nucleotides” were pre-sented by Thomas E. Young, MD from the University of North Carolina, and David H. Adamkin, MD from the University of Louisville, respectively. Dr. Young reported that nutritional support in the extremely low birth weight (ELBW) neonate plays a role in the prevention, and amelioration of, and recovery from BPD, and that no evidence-based guidelines cur-rently exist for the nutritional man-agement of BPD patients. Specific nutrients likely have a role in the pre-vention and treatment as well as catch-up growth in patients with BPD. Overall, Dr. Young concluded that these patients require appropriately fortified breast milk.

Finally, Dr. Adamkin focused on the trials that provided evidence that docosahexaenoic acid (DHA) and

arachidonic acid (ARA) supplementa-tion of formulas may increase visual acuity and impact neurodevelopment. He stated that, although the evidence on neurodevelopment of these sub-stances in the term neonate is less convincing, this issue needs further investigation. In support of this statement, Dr. Adamkin reviewed some of the available analysis from the Cochrane Database and stated that although most trials could not find significant effects on neurodevel-opment or growth following supple-mentation with long-chain polyun-saturated fatty acids, some indirect evidence suggests otherwise. Fi-nally, Dr. Adamkin presented some of the evidence on the immunoprotec-tive effects of human milk, and con-cluded that human milk has unmatch-able components, and biological vari-ability, and that it contains more than just nutrients. Regarding this last point he warned that the bioavailabil-ity of nutrients present in human milk may be altered by processing and that this issue needs to be consid-ered when deciding the most appro-priate form of nutritional support in the preterm or term neonate.

Istvan Seri, MD, PhD USC Keck School of Medicine Children’s Hospital of Los Angeles Los Angeles, CA USA 2006 Program Chair and Steering Committee Member

“The next ‘Evidence vs. Experience in Neonatal Practices Conference’ will be held in Chicago, IL on June 22nd and 23rd, 2007 returning to the city of the inaugural meeting. As it becomes available, more information regarding the 2007 program can be obtained at the meeting web site at www.5StarMedEd.org/neonatal or by calling Nina Pratt at 760-773-4500 or toll free at 800-321-3690, 8:00 am to 5:00 pm, Pacific Time.”

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